chr17-79106690-G-A

Variant names:

• chr17-79106690-G-A
• rs150282906
• NM_001350451.2:c.321C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001385804.1(RBFOX3):​c.321C>T​(p.Pro107Pro) variant causes a synonymous change. The variant allele was found at a frequency of 0.00154 in 1,489,880 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (26 hom.)
• Consequence: RBFOX3 NM_001385804.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.48
• Publications: 2 publications found

Genes affected

RBFOX3 (HGNC:27097): (RNA binding fox-1 homolog 3) This gene encodes a member of the RNA-binding FOX protein family which is involved in the regulation of alternative splicing of pre-mRNA. The protein has an N-terminal proline-rich region, an RNA recognition motif (RRM) domain, and a C-terminal alanine-rich region. This gene produces the neuronal nuclei (NeuN) antigen that has been widely used as a marker for post-mitotic neurons. This gene has its highest expression in the central nervous system and plays a prominent role in neural tissue development and regulation of adult brain function. Mutations in this gene have been associated with numerous neurological disorders. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2017]

RBFOX3 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-79106690-G-A is Benign according to our data. Variant chr17-79106690-G-A is described in ClinVar as Benign. ClinVar VariationId is 238284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00288 (439/152284) while in subpopulation EAS AF = 0.0186 (96/5174). AF 95% confidence interval is 0.016. There are 5 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 439 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385804.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	NM_001350451.2	MANE Select	c.321C>T	p.Pro107Pro	synonymous	Exon 6 of 15	NP_001337380.1
	RBFOX3	NM_001385804.1		c.321C>T	p.Pro107Pro	synonymous	Exon 6 of 15	NP_001372733.1
	RBFOX3	NM_001385805.1		c.321C>T	p.Pro107Pro	synonymous	Exon 7 of 16	NP_001372734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX3	ENST00000693108.1	MANE Select	c.321C>T	p.Pro107Pro	synonymous	Exon 6 of 15	ENSP00000510395.1
	RBFOX3	ENST00000857749.1		c.417C>T	p.Pro139Pro	synonymous	Exon 6 of 15	ENSP00000527808.1
	RBFOX3	ENST00000583458.5	TSL:5	c.318C>T	p.Pro106Pro	synonymous	Exon 5 of 14	ENSP00000464186.1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152164 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00380 AC: 361 AN: 95036 AF XY: 0.00335

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0148

Gnomad FIN exome AF: 0.00258

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00139 AC: 1853 AN: 1337596 Hom.: 26 Cov.: 31 AF XY: 0.00131 AC XY: 866 AN XY: 658904

African (AFR) AF: 0.000260 AC: 7 AN: 26960

American (AMR) AF: 0.0258 AC: 540 AN: 20966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22824

East Asian (EAS) AF: 0.0270 AC: 841 AN: 31158

South Asian (SAS) AF: 0.000172 AC: 12 AN: 69818

European-Finnish (FIN) AF: 0.00251 AC: 122 AN: 48512

Middle Eastern (MID) AF: 0.000549 AC: 3 AN: 5468

European-Non Finnish (NFE) AF: 0.000196 AC: 207 AN: 1056446

Other (OTH) AF: 0.00218 AC: 121 AN: 55444

GnomAD4 genome AF: 0.00288 AC: 439 AN: 152284 Hom.: 5 Cov.: 33 AF XY: 0.00329 AC XY: 245 AN XY: 74464

African (AFR) AF: 0.000265 AC: 11 AN: 41562

American (AMR) AF: 0.0178 AC: 272 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0186 AC: 96 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68004

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000687 Hom.: 0

Bravo AF: 0.00405

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Idiopathic generalized epilepsy (1)
-	-	1	not provided (1)
-	-	1	RBFOX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		4.5
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150282906; hg19: chr17-77102772;